Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression
Abstract Dysregulation of the alternative pathway (AP) of the complement system is a significant contributor to age-related macular degeneration (AMD), a primary cause of irreversible vision loss worldwide. Here, we assess the contribution of the liver-produced complement factor H-related 4 protein...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44605-0 |
| _version_ | 1827382128778674176 |
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| author | M. A. Zouache B. T. Richards C. M. Pappas R. A. Anstadt J. Liu T. Corsetti S. Matthews N. A. Seager S. Schmitz-Valckenberg M. Fleckenstein W. C. Hubbard J. Thomas J. L. Hageman B. L. Williams G. S. Hageman |
| author_facet | M. A. Zouache B. T. Richards C. M. Pappas R. A. Anstadt J. Liu T. Corsetti S. Matthews N. A. Seager S. Schmitz-Valckenberg M. Fleckenstein W. C. Hubbard J. Thomas J. L. Hageman B. L. Williams G. S. Hageman |
| author_sort | M. A. Zouache |
| collection | DOAJ |
| description | Abstract Dysregulation of the alternative pathway (AP) of the complement system is a significant contributor to age-related macular degeneration (AMD), a primary cause of irreversible vision loss worldwide. Here, we assess the contribution of the liver-produced complement factor H-related 4 protein (FHR-4) to AMD initiation and course of progression. We show that FHR-4 variation in plasma and at the primary location of AMD-associated pathology, the retinal pigment epithelium/Bruch’s membrane/choroid interface, is entirely explained by three independent quantitative trait loci (QTL). Using two distinct cohorts composed of a combined 14,965 controls and 20,741 cases, we ascertain that independent QTLs for FHR-4 are distinct from variants causally associated with AMD, and that FHR-4 variation is not independently associated with disease. Additionally, FHR-4 does not appear to influence AMD progression course among patients with disease driven predominantly by AP dysregulation. Modulation of FHR-4 is therefore unlikely to be an effective therapeutic strategy for AMD. |
| first_indexed | 2024-03-08T14:15:05Z |
| format | Article |
| id | doaj.art-5509274071cb4770a0b493d6e99eb582 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T14:15:05Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-5509274071cb4770a0b493d6e99eb5822024-01-14T12:28:28ZengNature PortfolioNature Communications2041-17232024-01-0115111710.1038/s41467-023-44605-0Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progressionM. A. Zouache0B. T. Richards1C. M. Pappas2R. A. Anstadt3J. Liu4T. Corsetti5S. Matthews6N. A. Seager7S. Schmitz-Valckenberg8M. Fleckenstein9W. C. Hubbard10J. Thomas11J. L. Hageman12B. L. Williams13G. S. Hageman14Sharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of UtahSharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of UtahSharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of UtahSharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of UtahSharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of UtahSharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of UtahSharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of UtahSharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of UtahSharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of UtahSharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of UtahSharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of UtahSharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of UtahSharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of UtahSharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of UtahSharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of UtahAbstract Dysregulation of the alternative pathway (AP) of the complement system is a significant contributor to age-related macular degeneration (AMD), a primary cause of irreversible vision loss worldwide. Here, we assess the contribution of the liver-produced complement factor H-related 4 protein (FHR-4) to AMD initiation and course of progression. We show that FHR-4 variation in plasma and at the primary location of AMD-associated pathology, the retinal pigment epithelium/Bruch’s membrane/choroid interface, is entirely explained by three independent quantitative trait loci (QTL). Using two distinct cohorts composed of a combined 14,965 controls and 20,741 cases, we ascertain that independent QTLs for FHR-4 are distinct from variants causally associated with AMD, and that FHR-4 variation is not independently associated with disease. Additionally, FHR-4 does not appear to influence AMD progression course among patients with disease driven predominantly by AP dysregulation. Modulation of FHR-4 is therefore unlikely to be an effective therapeutic strategy for AMD.https://doi.org/10.1038/s41467-023-44605-0 |
| spellingShingle | M. A. Zouache B. T. Richards C. M. Pappas R. A. Anstadt J. Liu T. Corsetti S. Matthews N. A. Seager S. Schmitz-Valckenberg M. Fleckenstein W. C. Hubbard J. Thomas J. L. Hageman B. L. Williams G. S. Hageman Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression Nature Communications |
| title | Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression |
| title_full | Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression |
| title_fullStr | Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression |
| title_full_unstemmed | Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression |
| title_short | Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression |
| title_sort | levels of complement factor h related 4 protein do not influence susceptibility to age related macular degeneration or its course of progression |
| url | https://doi.org/10.1038/s41467-023-44605-0 |
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